Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral administration. Eli Lilly markets duloxetine in the United States under the trade name Cymbalta® as a delayed release capsule containing enteric-coated pellets of the duloxetine. It is indicated for the treatment of major depressive disorder and for the treatment of diabetic peripheral neuropathic pain. These enteric-coated pellets are designed to prevent degradation of the drug in the acidic environment of the stomach.
Duloxetine is acid labile and acid hydrolysis of its ether linkage results in a thienyl alcohol and 1-naphthol. 50% of the dosage is hydrolyzed to 1-naphthol within one hour at a pH of 1.0, which is achieved under fasting conditions. At a pH of 2.0, 10% of the dosage degrades to 1-naphthol in one hour and at a pH of 4.0, 10% degradation would take up to 63 hours. Typically, such acid sensitive compounds are formulated as enteric-coated pellets to protect them from degradation.
The enteric dosage forms have been employed to protect the duloxetine from degradation because it is very important that duloxetine should not be exposed to gastric acid prior to absorption. Although it is stable at alkaline pH, it gets destroyed rapidly as pH falls. Therefore, if the micro encapsulation or the enteric coating is disrupted (e.g., by trituration of the compound or chewing the capsule), the duloxetine would be exposed to degradation by the gastric acid in the stomach. Duloxetine was also found to react with many enteric coatings to form a slowly- or even insoluble coating.
U.S. Pat. No. 5,508,276 discloses duloxetine in the form of enteric pellets. The enteric pellet includes a core containing duloxetine and an enteric layer which includes hydroxypropylmethylcellulose acetate succinate.
US Application No. 20060165776 discloses a composition containing a core consisting of duloxetine or its derivatives, the core includes pharmaceutically inert nuclei and duloxetine or its derivatives compressed together, an intermediate and an enteric layer, wherein the composition is free of alkaline reacting compounds.
US Application No. 20070004795 discloses compositions of duloxetine with buffering agents.
US Application No. 20060079569 discloses oral liquid compositions of duloxetine or its derivatives thereof.
US Application No. 20070292511 discloses delayed release compositions of duloxetine or salts thereof with enteric layer which includes methacrylic acid copolymer and hydroxypropyl methylcellulose phthalate.
The present invention addresses and overcomes the above commonly encountered degradation problems with the formulations of duloxetine.